Gas Phase Deposition Technique for Preparation of Pharmaceutical Compositions

This invention relates to a new process for the manufacture of compositions that are useful in the field of drug delivery.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.

In the field of drug delivery, the ability to control the profile of drug release is of critical importance. It is desirable to ensure that active ingredients are released at a desired and predictable rate in vivo following administration, in order to ensure a more optimal pharmacokinetic profile.

In the case of sustained release compositions, it is of critical importance that a drug delivery composition provides a release profile that shows minimal initial rapid release of active ingredient, that is a large concentration of drug in plasma shortly after administration. Such a ‘burst’ release may be hazardous in the case of drugs that have a narrow therapeutic window or drugs that are toxic at high plasma concentrations.

In the case of an injectable suspension of an active ingredient, it is also important that the size of the suspended particles is controlled so that they can be injected through a needle. If large, aggregated particles are present, they will not only block the needle, through which the suspension is to be injected, but also will not form a stable suspension within (i.e. they will instead tend to sink to the bottom of) the injection liquid.

There is, thus, a general need in the art for effective and/or improved drug transport and delivery systems.

Atomic layer deposition (ALD) is a technique that is employed to deposit thin films comprising a variety of materials, including organic, biological, polymeric and, especially, Inorganic materials, such as metal oxides, on solid substrates. It is an enabling technique for atomic and close-to-atomic scale manufacturing (ACSM) of materials, structures, devices and systems in versatile applications (see, for example, Zhang et al.2022, https://doi.org/10.1007/s41871-022-00136-8). Based on its self-limiting characteristics, ALD can achieve atomic-level thickness that is only controlled by adjusting the number of growth cycles. Moreover, multilayers can be deposited, and the properties of each layer can be customized at the atomic level.

Due to its atomic-level control, ALD is used as a key technique for the manufacturing of, for example, next-generation semiconductors, or in atomic-level synthesis of advanced catalysts as well as in the precise fabrication of nanostructures, nanoclusters, and single atoms (see, for example, Zhang et al. vide supra).

The technique is usually performed at low pressures and elevated temperatures. Film coatings are produced by alternating exposure of solid substrates within an ALD reactor chamber to vaporized reactants in the gas phase. Substrates can be silicon wafers, granular materials or small particles (e.g. microparticles or nanoparticles).

The coated substrate is protected from chemical reactions (decomposition) and physical changes by the solid coating. ALD can also potentially be used to control the rate of release of the substrate material within a solvent, which makes it of potential use in the formulation of active pharmaceutical ingredients.

In ALD, a first precursor, which can be metal-containing, is fed into an ALD reactor chamber (in a so called ‘precursor pulse’), and forms an adsorbed atomic or molecular monolayer at the surface of the substrate. Excess first precursor is then purged from the reactor, and then a second precursor, such as water, is pulsed into the reactor. This reacts with the first precursor, resulting in the formation of a monolayer of e.g. metal oxide on the substrate surface. A subsequent purging pulse is followed by a further pulse of the first precursor, and thus the start of a new cycle of the same events (a so called ‘ALD cycle’).

Alternatively, in ‘spatial ALD’, separate reactor chambers contain each precursor and the substrate being coated is moved from one reactor chamber to another in order for a coating to be formed. In this, or other methods of ALD, the introduction of a precursor to the substate being coated (or vice versa) may be considered equivalent to a ‘precursor pulse’ and the separation of a precursor from the substrate to be coated (or vice versa) may be considered equivalent to a ‘purging pulse’.

The thickness of the film coating is controlled by inter alia the number of ALD cycles that are conducted.

In a normal ALD process, because only atomic or molecular monolayers are produced during any one cycle, no discernible physical interface is formed between these monolayers, which essentially become a continuum at the surface of the substrate.

In international patent application WO 2014/187995, a process is described in which a number of ALD cycles are performed, which is followed by periodically removing the resultant coated substrates from the reactor and conducting a re-dispersion/agitation step to present new surfaces available for precursor adsorption.

The agitation step is done primarily to solve a problem observed for nano- and microparticles, namely that, during the ALD coating process, aggregation of particles takes place, resulting in ‘pinholes’ being formed by contact points between such particles. The re-dispersion/agitation step was performed by placing the coated substrates in water and sonicating, which resulted in deagglomeration, and the breaking up of contact points between individual particles of coated active substance.

The particles were then loaded back into the reactor and the steps of ALD coating of the powder, and deagglomerating the powder were repeated 3 times, to a total of 4 series of cycles. This process has been found to allow for the formation of coated particles that are, to a large extent, free of pinholes (see also, Hellrup et al.,529, 116 (2017)).

It has been found that the process of carrying out of ‘sets’ of ALD coating cycles followed by intermittent dispersion, as described in WO 2014/187995, results in clear, separate layers of coatings that are defined by clear, visible, physical interfaces between such coating layers. Such interfaces are more distinct than interfaces that can be seen between layers of different coating materials. The interfaces that form by such intermittent dispersion of the particles are clearly visible by a technique such as transmission electron microscopy (TEM) as regions of higher electron permeability. As explained below, similar interfaces are not visible when coatings of the same material are built up one atomic layer at a time from the surface of a substrate.

As described in international patent application WO 2021/111149, we have more recently found that it is advantageous to deagglomerate aggregated particles into primary particles externally to the reactor by a dry process that involves a combination of a mechanical forcing means and a sieve (in particular a sonic sifting device). This avoids the need for employing an aggressive deagglomeration technique such as sonication, as well as the need to dry particles prior to placing them back into the reactor for further coating. We have found that conducting the deagglomeration steps in this way allows for the presentation of essentially completely pinhole-free coated particles in a form that can be readily processed into a pharmaceutical formulation.

As described in unpublished UK patent application no. GB 2108305.0, we have even more recently found that it is advantageous to use a vibrational sieving technique to deagglomerate aggregated particles. In particular, the vibrational sieving technique results in the deagglomerated coated particles with the essential absence of cracks through which active ingredient can be released in an uncontrolled way.

In attempting to further scale up the processes described in WO 2021/111149 and UK patent application no. GB 2108305.0, we have found that the consistency of coatings between different particles coated together can become unsatisfactory as larger scale continuous flow reactors are used. This problem has been unexpectedly solved by way of the process described herein.

According to a first aspect of the invention there is provided a process for the preparation of composition in the form of a plurality of particles, which process comprises:

In the process of the invention, both the first reactant gas and the second reactant gas, respectively, are allowed to contact the particle for a pre-determined period of soaking time. The term ‘soaking’ is used in this application only for clarity, that is, so that the relevant pre-determined period of time is readily distinguishable from other pre-determined periods of time that may be mentioned in the application. It is to be understood that the term ‘soaking’ is in no way limits the associated pre-determined period of time.

The process having such a soaking time increases the coating uniformity (also referred to as coating integrity or shell integrity, which may be measured for example as described hereinafter) because it allows each gas to diffuse conformally in high aspect-ratio substrates, e.g. especially powders. This is due to the substrates having an Increased surface area which needs a longer period of time to disuse and react with all of the available surface sites.

The aforementioned benefit of including a soaking time is even more pronounced when the process involves the use of reactants with slow reactivity because more time is provided for the reactant to react on the substrate surface. For example, this is evident especially for diethylzinc (DEZ) when depositing AlZnO as its reaction probability towards the surface is lower than for example trimethylaluminum (TMA).

Known ALD processes run in a continuous flow manner, meaning that a pump is actively pumping on the reactor during the whole process and gases pass continuously over the powder substrate. In contrast, including a soaking time in the process prevents the continuous flow of gases over the powder substrate. For example, introducing a soaking time may include closing a valve to prevent either inflow or outflow from the reactor chamber. If a valve is closed to prevent inflow (e.g. the valve is positioned to close an inlet to the reactor chamber), pressure in the reactor chamber may be substantially constant during the soaking time. However, some change in pressure may occur due to reactions taking place and the pressure change would depend on the stoichiometry of those reactions. Alternatively, if a valve is closed to prevent outflow (e.g. the valve is positioned to close an outlet of the reactor chamber), pressure in the reactor chamber may steadily increase during the soaking time as more precursor enters the reactor chamber. This may beneficially urge the precursor further into the powder bed and increase the likelihood of reaction with the surfaces of particles therein, thereby enhancing the effect of the soaking time.

An ALD process including such soaking times is sometimes referred to as a “stop-flow” process.

The inclusion of a soaking time will not only generate coatings with good shell integrity and more controlled release profiles but it also gives a coating composition closer towards the ALD process setup. When using an ALD cycle scheme consisting of three DEZ cycles and one TMA cycle one would expect to get an atomic ratio of 3:1 between Zn and Al in the resulting shell. This is not the case when depositing with continuous flow, where the atomic ratio nears 1:1 because of the lower reaction probability for DEZ than TMA. When using stop-flow the same ratio is very close to 3:1.

The process of the invention also requires using a stationary gas phase deposition reactor chamber. It will be understood that a stationary reactor chamber in the context of the invention is a reactor chamber that remains stationary while in use to perform a gas phase deposition technique, excluding negligible vibrations caused by associated machinery. This is in contrast to a reactor chamber which rotates or vibrates or otherwise actively moves during the gas phase deposition process.

It will be understood that the “pre-determined period” of soaking time may be any suitable period of time. The period of time is largely dependent on the particle sample size (or batch size), wherein the smaller the sample size the less soaking time is required whilst the larger the sample size the longer soaking time is required. The soaking time may also be dependent on factors such as the characteristics of the solid cores and/or the type of reactant gas. Additionally, the soaking time may depend on the design of the ALD reactor, e.g., size of the reaction chamber, distance to the inlet valves and the valve to the pump. The soaking time may be in range of about 2 seconds to about 30 minutes. For example, the soaking time may be about 30 seconds, 1 minute, 3 minutes, 10 minutes or 15 minutes.

It will be appreciated by a person skilled in the art that, for any combination of variables mentioned above, the beneficial effect provided by a soaking time is finite. For example, for a given process, a first 5 second period of a soaking time may provide a significant benefit to coating uniformity and integrity, a second 5 second period of soaking time may provide some additional benefit but less than that provided by the first period and a third 5 second period may be an almost negligible additional benefit over the benefit that had already been gained (this is a simplified example for demonstrative purposes only). In other words. It is predicted that the benefit provided by soaking time as the soaking time is increased can be modelled as a curve that increases with a high gradient initially but the gradient will reduce as the soaking time is increased until a steady state is eventually reached at which point further soaking may no longer be advantageous.

Although the ‘benefit’ of a soaking time is not limited to shell integrity, it will be appreciated that the shell integrity of resulting particles may be used as an indicator of the effectiveness of the soaking time. Accordingly, to select a suitable soaking time for a particular process, a person skilled in the art may run trials including incrementally increasing soaking times to determine a desirable compromise between the length of soaking time and the benefit it provides to shell integrity. In the simplified example referred to above, the skilled person may determine that a soaking time close to 10 seconds is appropriate as minimal additional benefit would be observed with any greater soaking time.

In some examples of the invention, the predetermined period of soaking time may be selected to provide a shell integrity, as measured for example as described hereinafter of at least about 70%, such as at least about 80%, such as at least about 90%, such as at least about 95%, such as about 98.5%. It is to be understood that shell or coating integrity, as described herein, may be considered as the inverse of API dissolution in a solvent which dissolves the API but not the coating material. For example, API dissolution of about 5% would be indicative of a shell/coating integrity of about 95%. Suitable methods for determining coating integrity via determination of API dissolution are provided in the examples described below.

During the process of the invention, the valve to the pump inlet is closed so that the reactant gas resides in the reaction chamber without any active pumping for the pre-determined soaking time before the chamber is then pumped. Depending on the reactor, the valve may be completely shut off so that no gas is passed through, or it may not be possible to completely shut off the valve such that there is the presence of minimal amount of pumping (e.g. a nitrogen carrier gas may still flow in the chamber), In either scenario, it is understood that no active pumping is occurring, That is to say, there is the substantial absence of pumping.

Moreover, the pre-determined period of soaking time is preferably carried out in the substantial absence of mechanical agitation of the plurality of solid cores. Agitation or sieving of the solid cores may take place during the other steps of the process, as described further on in this application.

The process may optionally include carrying out multipulses, i.e. short burst of in-flow, of the reactant gas without purging/rinsing in between each multipulse, with each multipulse pumping the reactor for a pre-determined period of pumping time. Such multipulsing is equivalent to carrying out a single long pulse of reactant gas in terms of the amount of reactant substrate that is applied to the solid cores. By applying the reactant in a multipulse manner, a more consistent coverage of the solid cores is achieved, Each multipulse pumping time may be from about 0.1 to 1000 seconds, about 1 to 500 seconds, about 2 to 250 seconds, about 3 to 100 seconds, about 4 to 50 seconds, or about 5 to 10 seconds, for example 9 seconds. The multipulses may be applied about 5 to 1000 times, about 10 to 250 times, or about 20 to 50 times in a single step.

The term ‘solid’ will be well understood by those skilled in the art to include any form of matter that retains its shape and density when not confined, and/or in which molecules are generally compressed as tightly as the repulsive forces among them will allow. The solid cores have at least a solid exterior surface onto which a layer of coating material can be deposited. The interior of the solid cores may be also solid or may instead be hollow. For example, if the particles are spray dried before they are placed into the reactor vessel, they may be hollow due to the spray drying technique. Cores may in the alternative comprise agglomerates of smaller ‘primary’ particles, i.e. secondary particles of a size range defined herein, which are subsequently coated as described herein.

The process of the invention is preferably employed to make pharmaceutical compositions. Accordingly, the composition, and in particular the solid cores, comprise a pharmacologically-effective amount of a biologically active agent.

In this respect, the solid cores may consist essentially of, or comprise, biologically active agent (which agent may hereinafter be referred to interchangeably as a ‘drug’, and ‘active pharmaceutical ingredient (API)’ and/or an ‘active ingredient’). Biologically active agents also include biopharmaceuticals and/or biologics. Biologically active agents can also include a mixture of different APIs, as different API particles or particles comprising more than one API.

By ‘consists essentially’ of biologically-active agent, we include that the solid core is essentially comprised only of biologically active agent(s), i.e. it is free from non-biologically active substances, such as excipients, carriers and the like (vide infra), and from other active substances. This means that the core may comprise less than about 5%, such as less than about 3%, including less than about 2%, e.g. less than about 1% of such other excipients and/or active substances.

In the alternative, cores comprising biologically active agents may include such an agent in admixture with one or more pharmaceutical ingredients, which may include pharmaceutically-acceptable excipients, such as adjuvants, diluents or carriers, and/or may include other biologically-active ingredients.

Biologically active agents may be presented in a crystalline, a part-crystalline and/or an amorphous state. Biologically active agents may further comprise any substance that is in the solid state, or which may be converted into the solid state, at about room temperature (e.g. about 18° C.) and about atmospheric pressure, irrespective of the physical form. Such agents (and optionally other pharmaceutical Ingredients as mentioned herein) should also remain in the form of a solid whilst being coated in, for example, an ALD reactor and also should not decompose physically or chemically to an appreciable degree (i.e. no more than about 10% w/w) whilst being coated, or after having been covered by at least one of the coating material. Biologically active agents may further be presented in combination (e.g. in admixture or as a complex) with another active substance.

As used herein, the term ‘biologically active agent’, or similar and/or related expressions, generally refer(s) to any agent, or drug, capable of producing some sort of physiological effect (whether in a therapeutic or prophylactic capacity against a particular disease state or condition) in a living subject, including, in particular, mammalian and especially human subjects (patients).

Biologically-active agents may, for example, be selected from an analgesic, an anaesthetic, an anti-ADHD agent, an anorectic agent, an antiaddictive agent, an antibacterial agent, an antimicrobial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, an antiprotozoal agent, an anthelmintic, an ectoparasiticide, a vaccine, an anticancer agent, an antimetabolite, an alkylating agent, an antineoplastic agent, a topoisomerase inhibitor, an immunomodulator, an immunostimulant, an immunosuppressant, an anabolic steroid, an anticoagulant agent, an antiplatelet agent, an anticonvulsant agent, an antidementia agent, an antidepressant agent, an antidote, an antihyperlipidemic agent, an antigout agent, an antimalarial, an antimigraine agent, an antiparkinson agent, an antipruritic agent, an antipsoriatic agent, an antiemetic, an anti-obesity agent, an antiasthma agent, an antibiotic, an antidiabetic agent, an antiepileptic, an antifibrinolytic agent, an antihemorrhagic agent, an antitussive, an antihypertensive agent, an antimuscarinic agent, an antimycobacterial agent, an antioxidant agent, an antipsychotic agent, an antipyretic, an antirheumatic agent, an antiarrhythmic agent, an anxiolytic agent, an aphrodisiac, a cardiac glycoside, a cardiac stimulant, an entheogen, an entactogen, an euphoriant, an orexigenic, an antithyroid agent, an anxiolytic sedative, a hypnotic, a neuroleptic, an astringent, a bacteriostatic agent, a beta blocker, a calcium channel blocker, an ACE inhibitor, an angiotensin II receptor antagonist, a renin inhibitor, a beta-adrenoceptor blocking agent, a blood product, a blood substitute, a bronchodilator, a cardiac inotropic agent, a chemotherapeutic, a coagulant, a corticosteroid, a cough suppressant, a diuretic, a deliriant, an expectorant, a fertility agent, a sex hormone, a mood stabilizer, a mucolytic, a neuroprotective, a nootropic, a neurotoxin, a dopaminergic, an antiparkinsonian agent, a free radical scavenging agent, a growth factor, a fibrate, a bile acid sequestrants, a cicatrizant, a glucocorticoid, a mineralcorticoid, a haemostatic, a hallucinogen, a hypothalamic-pituitary hormone, an immunological agent, a laxative agent, an antidiarrheals agent, a lipid regulating agent, a muscle relaxant, a parasympathomimetic, a parathyroid calcitonin, a serenic, a statin, a stimulant, a wakefulness-promoting agent, a decongestant, a dietary mineral, a biphosphonate, a cough medicine, an ophthamological, an ontological, a H1 antagonist, a H2 antagonist, a proton pump inhibitor, a prostaglandin, a radio-pharmaceutical, a hormone, a sedative, an anti-allergic agent, an appetite stimulant, a steroid, a sympathomimetic, a thrombolytic, a thyroid agent, a vasodilator, a xanthine, an erectile dysfunction improvement agent, a gastrointestinal agent, a histamine receptor antagonist, a keratolytic, an antlanginal agent, a non-steroidal antiinflammatory agent, a COX-2 inhibitor, a leukotriene inhibitor, a macrolide, a NSAID, a nutritional agent, an opioid analgesic, an opioid antagonist, a potassium channel activator, a protease inhibitor, an antiosteoporosis agent, a cognition enhancer, an antiurinary incontinence agent, a nutritional oil, an antibenign prostate hypertrophy agent, an essential fatty acid, a non-essential fatty acid, a radiopharmaceutical, a senotherapeutic, a vitamin, or a mixture of any of these.

The biologically-active agent may also be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, or a mixture thereof. Non-limiting examples of therapeutic peptides/proteins are as follows: lepirudin, cetuximab, dornase alfa, denileukin diftitox, etanercept, bivalirudin, leuprolide, alteplase, interferon alfa-n1, darbepoetin alfa, reteplase, epoetin alfa, salmon calcitonin, interferon alfa-n3, pegfilgrastim, sargramostim, secretin, peginterferon alfa-2b, asparaginase, thyrotropin alfa, antihemophilic factor, anakinra, gramicidin D, intravenous immunoglobulin, anistreplase, insulin (regular), tenecteplase, menotropins, interferon gamma-1b, interferon alfa-2a (recombinant), coagulation factor VIIa, oprelvekin, palifermin, glucagon (recombinant), aldesleukin, botulinum toxin Type B, omalizumab, lutropin alfa, insulin lispro, insulin glargine, collagenase, rasburicase, adalimumab, Imiglucerase, abciximab, alpha-1-proteinase inhibitor, pegaspargase, interferon beta-1a, pegademase bovine, human serum albumin, eptifibatide, serum albumin iodinated, infliximab, follitropin beta, vasopressin, interferon beta-1b, hyaluronidase, rituximab, basiliximab, muromonab, digoxin immune Fab (ovine), ibritumomab, daptomycin, tositumomab, pegvisomant, botulinum toxin type A, pancrelipase, streptokinase, alemtuzumab, alglucerase, capromab, laronidase, urofollitropin, efalizumab, serum albumin, choriogonadotropin alfa, antithymocyte globulin, filgrastim, coagulation factor IX, becaplermin, agalsidase beta, interferon alfa-2b, oxytocin, enfuvirtide, palivizumab, daclizumab, bevacizumab, arcitumomab, eculizumab, panitumumab, ranibizumab, idursulfase, alglucosidase alfa, exenatide, mecasermin, pramlintide, galsulfase, abatacept, cosyntropin, corticotropin, insulin aspart, insulin detemir, insulin glulisine, pegaptanib, nesiritide, thymalfasin, defibrotide, natural alpha interferon/multiferon, glatiramer acetate, preotact, teicoplanin, canakinumab, ipilimumab, sulodexide, tocilizumab, teriparatide, pertuzumab, rilonacept, denosumab, liraglutide, semaglutide, exenatide, lixisenatide, albiglutide, dulaglutide, tirzepatide, golimumab, belatacept, buserelin, velaglucerase alfa, tesamorelin, brentuximab vedotin, belimumab, aflibercept, taliglucerase alfa, asparaginase, ocriplasmin, glucarpidase, teduglutide, raxibacumab, certolizumab pegol, insulin isophane, epoetin zeta, obinutuzumab, fibrinolysin aka plasmin, follitropin alpha, romiplostim, lucinactant, natalizumab, aliskiren, ragweed pollen extract, secukinumab, somatotropin (recombinant), drotrecogin alfa, alefacept, OspA lipoprotein, urokinase, abarelix, sermorelin, aprotinin, gemtuzumab ozogamicin, satumomab pendetide, antithrombin alfa, antithrombin III (human), asfotase alfa, atezolizumab, autologous cultured chondrocytes, beractant, blinatumomab, C1 esterase inhibitor (human), coagulation factor XIII A-subunit (recombinant), conestat alfa, daratumumab, desirudin, elosulfase alfa, evolocumab, fibrinogen concentrate (human), filgrastim-sndz, gastric intrinsic factor, hepatitis B immune globulin, human calcitonin, humantoxoid immune globulin, human rabies virus immune globulin, human Rho (D) immune globulin, human Rho (D) immune globulin, hyaluronidase (human, recombinant), idarucizumab, immune globulin (human), vedolizumab, ustekinumab, turoctocog alfa, tuberculin purified protein derivative, simoctocog alfa, siltuximab, sebelipase alfa, sacrosidase, ramucirumab, prothrombin complex concentrate, poractant alfa, pembrolizumab, peginterferon beta-1a, ofatumumab, obiltoxaximab, nivolumab, necitumumab, metreleptin, methoxy polyethylene glycol-epoetin beta, mepolizumab, ixekizumab, insulin degludec, insulin (porcine), insulin (bovine), thyroglobulin, anthrax immune globulin (human), anti-inhibitor coagulant complex, brodalumab, C1 esterase inhibitor (recombinant), chorionic gonadotropin (human), chorionic gonadotropin (recombinant), coagulation factor X (human), dinutuximab, efmoroctocog alfa, factor IX complex (human), hepatitis A vaccine, human varicella-zoster immune globulin, ibritumomab tiuxetan, lenograstim, pegloticase, protamine sulfate, protein S (human), sipuleucel-T, somatropin (recombinant), susoctocog alfa and thrombomodulin alfa, as well as sarcomeres and synthetic forms of antisense RNA, RNA interference agent, messenger RNA, transfer RNA, ribosomal RNA, including RNA aptameres.

Non-limiting examples of drugs which may be used according to the present invention are all-trans retinoic acid (tretinoin), alprazolam, allopurinol, amiodarone, amlodipine, asparaginase, astemizole, atenolol, azathioprine, azelatine, beclomethasone, bendamustine, bleomycin, budesonide, buprenorphine, butalbital, capecitabine, carbamazepine, carbidopa, carboplatin, cefotaxime, cephalexin, chlorambucil, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclophosphamide, cyclosporin, cytarabine, dacarbazine, dactinomycin, daunorubicin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, docetaxel, doxorubicin, doxazosin, enalapril, epirubicin, erlotinib, estradiol, etodolac, etoposide, everolimus, famotidine, felodipine, fentanyl citrate, fexofenadine, filgrastim, finasteride, fluconazole, flunisolide, fluorouracil, flurbiprofen, fluralaner, fluvoxamine, furosemide, gemcitabine, glipizide, gliburide, ibuprofen, ifosfamide, imatinib, indomethacin, irinotecan, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, mercaptopurine, mesna, methotrexate, methylprednisolone, midazolam, mitomycin, mitoxantrone, moxidectine, mometasone, nabumetone, naproxen, nicergoline, nifedipine, norfloxacin, omeprazole, oxaliplatin, paclitaxel, phenyloin, piroxicam, procarbazine, quinapril, ramipril, risperidone, rituximab, sertraline, simvastatin, sulindac, sunitinib, temsirolimus, terbinafine, terfenadine, thioguanine, trastuzumab, triamcinolone, valproic acid, vinblastine, vincristine, vinorelbine, zolpidem, or pharmaceutically-acceptable salts of any of these.

Compositions made by the process of the invention may comprise benzodiazipines, such as alprazolam, chlordiazepoxide, clobazam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, quazepam, temazepam, triazolam and pharmaceutically-acceptable salts of any of these.

Anaesthetics that may also be employed in the compositions made by the process of the invention may be local or general. Local anaesthetics that may be mentioned include amylocaine, ambucaine, articaine, benzocaine, benzonatate, bupivacaine, butacaine, butanilicaine, chloroprocaine, cinchocaine, cocaine, cyclomethycaine, dibucaine, diperodon, dimethocaine, eucaine, etidocaine, hexylcaine, fomocaine, fotocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, nitracaine, orthocaine, oxetacaine, oxybuprocaine, paraethoxycaine, phenacaine, piperocaine, piridocaine, pramocaine, prilocaine, primacaine, procaine, procainamide, proparacaine, propoxycaine, pyrrocaine, quinisocaine, ropivacaine, trimecaine, tolycaine, tropacocaine, or pharmaceutically-acceptable salts of any of these.

Psychiatric drugs may also be employed in the compositions made by the process of the invention. Psychiatric drugs that may be mentioned include 5-HTP, acamprosate, agomelatine, alimemazine, amfetamine, dexamfetamine, amisulpride, amitriptyline, amobarbital, amobarbital/secobarbital, amoxapine, amphetamine(s), aripiprazole, asenapine, atomoxetine, baclofen, benperidol, bromperidol, bupropion, buspirone, butobarbital, carbamazepine, chloral hydrate, chlorpromazine, chlorprothixene, citalopram, clomethiazole, clomipramine, clonidine, clozapine, cyclobarbital/diazepam, cyproheptadine, cytisine, desipramine, desvenlafaxine, dexamfetamine, dexmethylphenidate, diphenhydramine, disulfiram, divalproex sodium, doxepin, doxylamine, duloxetine, enanthate, escitalopram, eszopiclone, fluoxetine, flupenthixol, fluphenazine, fluspirilen, fluvoxamine, gabapentin, glutethimide, guanfacine, haloperidol, hydroxyzine, iloperidone, imipramine, lamotrigine, levetiracetam, levomepromazine, levomilnacipran, lisdexamfetamine, lithium salts, lurasidone, melatonin, melperone, meprobamate, metamfetamine, nethadone, methylphenidate, mianserin, mirtazapine, moclobemide, naltrexone, nalmefene, niaprazine, nortriptyline, olanzapine, ondansetron, oxcarbazepine, paliperidone, paroxetine, penfluridol, pentobarbital, perazine, pericyazine, perphenazine, phenelzine, phenobarbital, pimozide, pregabalin, promethazine, prothipendyl, protriptyline, quetiapine, ramelteon, reboxetine, reserpine, risperidone, rubidium chloride, secobarbital, selegiline, sertindole, sertraline, sodium oxybate, sodium valproate, sodium valproate, sulpiride, thioridazine, thiothixene, tianeptine, tizanidine, topiramate, tranylcypromine, trazodone, trifluoperazine, trimipramine, tryptophan, valerian, valproic acid in 2.3:1 ratio, varenicline, venlafaxine, vilazodone, vortioxetine, zaleplon, ziprasidone, zolpidem, zopicione, zotepine, zuclopenthixol and pharmaceutically-acceptable salts of any of these.

Antiparkinsonism drugs that may be mentioned include levodopa and apomorphine and pharmaceutically-acceptable salts of these.